DE2837403A1 - IMPROVEMENTS OR ORGANIC COMPOUNDS - Google Patents

Description

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Improvements in or relating to organic compounds

The invention relates to a process for the production of quinazolin-2 (1H) -ones. The invention is a Process for the preparation of 4-aryl-quinazolin ~ 2 (IH) ones, especially of compounds of formula I,

in which R ₁ denotes a (C -C) hydrocarbon radical which is optionally mono-, di- or trisubstituted with fluorine, chlorine and bromine,

R _{0 represents} a monocyclic aryl and

R- and R. are identical or different and are each hydrogen, (C ₁ -C) alkyl or alkoxy, fluorine,

Mean chlorine, bromine or trifluoromethyl or R and R together represent a 6,7-methylenedioxy group form,

by a corresponding 5,6,7,8-tetrahydro-2 (IH) quinazolinone - especially a compound - of formula II,

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II

in which R ₁ , R, R and R have the meanings mentioned above, is dehydrogenated with sulfur in an inert organic solvent, which is characterized in that the dehydrogenation takes place in the presence of an inorganic metal compound in the form of an oxide, hydroxide or salt and which Metal compound forms a metal sulfide under the reaction conditions, with the exception of magnesium, aluminum and alkali metal compounds.

The inventive method is advantageously carried out at 125 ° to 250 ⁰ C, preferably at 130 ° to 200 ⁰ C and especially at 135 ° - 200 ⁰ C executed.

The reaction is carried out in an organic solvent, inert under the reaction conditions. Preferred Solvents are e.g. ethylene glycol, propylene glycol, ethoxyethoxyethanol, dioxane, toluene, xylene and p-cymene.

A solvent is preferably used which boils at the desired reaction temperature, thus in the reflux process can be worked, e.g. p-cymene at the preferred reaction temperatures.

The molar ratio of sulfur to tetrahydroquinazolinone starting material, especially of compound II, can vary quite widely, but should be at least 1.7: 1

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gen. The upper limit is not particularly critical. However, it is unnecessary and not economical to have more sulfur to be used as determined by the 6: 1 molar ratio.

The molar ratio between 1.9: 1 and 4: 1 and preferably between 2: 1 and 3: 1 is advantageous.

The inorganic metal compound forms under the reaction conditions a sulfide.

For practical reasons, compounds of alkali metals, magnesium and aluminum are excluded as well those of rare earth metals and metals with an atomic weight of 84 or greater are not preferred.

Preferred metals are calcium, titanium, zirconium / chromium, lead, molybdenum, manganese, iron, tin, cobalt, nickel, Palladium, copper, silver, zinc, cadmium, mercury, antimony and bismuth? calcium is particularly preferred, Iron or zinc. The metal compound can be used as a salt present / e.g. as a salt of a strong acid, e.g. as a halide such as a chloride, or as a sulphate or nitrate, however, it is preferably an oxide or hydroxide, especially an oxide.

Preferred metal compounds are calcium oxide, zinc oxide and especially ferric oxide.

Some metal compounds that can be used, e.g. calcium chloride, react with hydrogen sulfide and form an acidic one Medium, the resulting metal sulfides tend to be unstable or soluble in this medium.

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In such cases, a basic hydroxide is preferably added to the reaction medium, for example an alkali metal or Alkaline earth metal hydroxide, or an excess of the inorganic metal compound, if this is a basic hydroxide is.

Preferably an alkali metal hydroxide such as potassium or sodium hydroxide is used.

The molar ratio of the metal compound to the compound II should be at least 1: 1. The upper limit is likewise not critical, although molar ratios above 10: 1 are of no advantage. The molar ratio is advantageous between 1.8: 1 and 6: 1, preferably between 2: 1 and 4: 1 and particularly between 2.1: 1 and 3: 1.

A basic hydroxide is used in a molar ratio of at least 1: 1, such as at least 1.5: 1, preferably 1.8 up to 6: 1 and especially 2 to 3: 1 used for compound II.

The process according to the invention is carried out under increased or reduced, preferably under atmospheric pressure executed. A gas envelope or constant gas flow over the reaction mixture and inert under the reaction conditions, e.g., nitrogen, is preferred.

The reaction takes about 1 to 15 hours.

The inventive method leads to significantly higher yields than the corresponding known method, the

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no anor ganis che-4ieiaJJLverbindjin_g ^ used "and where usually a mixture of the desired quinazolin-2- (IH) -one and the corresponding 3,4-dihydro derivative

The compounds II are either known per se or can be prepared from known starting materials by known methods getting produced.

In the compounds of formulas I and II is the

(C _n -C ₀ ) hydrocarbon radical of R _1, preferably (C ₁ -C,) Io χ Xb

Alkyl, (C ₃ -C ₇ ) cycloalkyl, (C ₄ -C ₇ ) cycloalkylalkyl with a (C -C) cycloalkyl and with a (C -C ₀ ) alkyl part, phenyl, benzyl or phenethyl.

R, is for example (C -C.) Alkyl, optionally mono-, di- or trisubstituted or phenyl, benzyl or phenethyl, optionally with fluorine, chlorine and bromine mono- or disubstituted.

The radicals which are substituted two or three times by halogen are preferably substituted by the same halogen atoms.

In the compounds of formulas I and II, R_ means preferably a radical of the formulas III or IV,

γ IV or N ^ Il ^Y 2

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in which Y and Y _{1 are} identical or different and are each hydrogen, fluorine, chlorine, bromine, (C ₁ -C ₃ ) alkyl or alkoxy, or trifluoromethyl, provided that if one of Y and Y is trifluoromethyl

represents, the other is hydrogen and Y "hydrogen, fluorine, chlorine, Denotes alkyl or alkoxy.

The compounds of the formula I are known, for example their anti-inflammatory activity is described. In this regard, R, preferably denotes (C, ~ C _r ) alkyl or

X Xb

Cyclopropylmethyl, especially (C _n -C ^) alkyl, especially iso-

J- D

propyl. R "is preferably phenyl, optionally mono- or disubstituted with fluorine, chlorine, bromine and especially phenyl or fluorophenyl. R and R. can be hydrogen.

In this regard, at least one of R ₃ and R is (C -C) alkyl, preferably methyl, for example in the 7-position or (C -C) alkoxy, for example methoxy, for example in the 6-position.

The compounds 7-methyl-1-isopropyl-4-phenyl-2 (IH) quinazolinone and 1-isopropyl-4-p-fluorophenyl-7-methyl-2 (1H) -quinazolinone are preferably prepared.

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Example 1: 7-methyl-1-isopropyl-4-phenyl-2 (IH) -quinaz olinone

A mixture of 200 ml of p-cymene, 40 g ferric oxide and 7 g of sulfur is heated to reflux of the solvent (about 175 ⁰ C), after which over 40 minutes dropwise to a hot (130 ° C) solution of 28.2 g. 7-methyl-1-isopropyl-4-phenyl-5,6,7,8-tetrahydro-2 (IH) quinazolinone in 200 ml of p-cymene is added. The resulting mixture is refluxed for 3 1/2 hours with 1.8 ml of water being collected in a Dean-Stark separator. The reaction solution is ^{cooled to 28 °} C. and placed on a cellulose acetate filter, which is washed four times with 25 ml of toluene each time. The toluene extracts are extracted with 50 ml and the p-cymene filtrate is extracted with 350 ml of 4N HCl. The acidic extracts are combined and extracted with 100 ml of toluene. The toluene extracts are eliminated. The acidic solution, which has been extracted with toluene, is treated with 350 ml of toluene and 110 g of a 50% aqueous sodium hydroxide solution. The phases are separated and the toluene phase is washed twice with 100 ml of water each time, dried over anhydrous sodium sulfate, filtered and evaporated dry in vacuo. The solid residue is dissolved in ethyl acetate and the title compound is obtained therefrom by crystallization (melting point 139-141 ° C.).

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Example 2 : 1-Isopropyl-4-p-fluorophenyl-7-methyl-2 (IH) -quinazolinone

A mixture of 67 ml of xylene, 13.3 g of ferric oxide and 2.5 g of sulfur is heated in nitrogen up to reflux of the solvent, whereafter for 20 minutes a hot (100-110 ⁰ C) solution of 10 g of 7-methyl-lisopropyl -4-p-fluorophenyl-5,6,7,8-tetrahydro-2 (IH) quinazolinone in 100 ml of xylene is added. The resulting mixture is refluxed for 10 hours with the solvent collecting water in a Dean-Stark separator. The reaction mixture is cooled to 80 ° C. and placed on a cellulose acetate filter and filtered.

The filtrate and the filter cake are washed three times with 50 ml of toluene each time. The filtrates are put together and extracted successively with 200, with 100 and with 50 ml of 4N HCl. The sour extracts will be put together and washed with 100 ml of toluene. The toluene extracts will be eliminated. The acidic solution, which has been extracted with toluene, is added with cooling and stirring 200 ml of toluene and 115 g of a 50% aqueous sodium hydroxide solution treated. The phases are separated and the aqueous phase is used twice each 100 ml of toluene washed.

The toluene phases are put together, washed twice with 100 ml of water each time, over anhydrous

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Dried magnesium sulfate, filtered through cellulose acetate filters, and concentrated to give 8.8 g (90%) of one yellow crystalline residue are formed. The residue is dissolved in ethyl acetate and the title compound obtained from it by crystallization. (M.p. 175-176.5 ° C)

Example 3: l ~ isogrogyl-4-phenyl-72ynethYl-2_ (lH ^ - quinozalinon

A mixture of 28.2 g of 7-methyl-1-isopropyl-4-phenyl-5,6,7,8-tetrahydro-2 (IH) -quinozalinone, 9.6 g of sulfur, 10 g of sodium hydroxide, 20 g of calcium chloride and 200 ml of 2- (2-ethoxyethoxy) ethanol is heated in nitrogen for 2 hours at 150 ⁰ C. The resulting mixture is cooled to 65 ⁰ C, 500 ml of benzene are added, and the mixture is cooled with stirring to 15 ° C, after which the liquid phase is decanted. The organic layer is washed with water and evaporated to give an oil which is dissolved in a mixture of 100 ml of benzene and 100 ml of 50% aqueous hydrochloric acid. The mixture is stirred for one hour at room temperature, the phases are separated and the acidic phase is treated with 50 ml of benzene. The acidic phase is neutralized with 50% sodium hydroxide solution, extracted with 150 ml of benzene, and the benzene extracts are washed with water until neutral. After drying over sodium sulfate, the benzene solution is evaporated and a crude product is obtained which is recrystallized from ethyl acetate and gives the title compound with a melting point of 141 ° -142 ° C.

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Example 4; ^ -Methyl-l-isopropyl - ^ - (p ~ f luophenyl) _- quinazolin-2_ (lH) -one

To a mixture of 4.3 g of sulfur, 6.8 g of zinc oxide and 67 ml of a xylene mixture which is heated under nitrogen to reflux (ca. 138 ° C), with stirring, a up to 100-115 ⁰ C preheated solution of 10.0 g of 7-methyl-1-isopropyl-4- (p-fluorophenyl) -5,6,7,8-tetra-hydro-2 (IH) -quinazolinone in 100 ml of a xylene mixture were added in 20 minutes, after which the resulting mixture is heated to reflux overnight ^ and cooled and filtered through cellulose acetate. The solid residue is washed with toluene, the filtrate and the washing liquid are treated four times with 4N HCl and the extracts are washed with 100 ml of toluene. The aqueous phase is treated with 200 ml of toluene and in portions with 115 g of 50% sodium hydroxide solution in an ice bath. The aqueous phase is extracted twice with 100 ml of toluene each time and the organic phase is washed with water and dried. After filtration and concentration in vacuo a solid product is obtained of a yellow color which was dissolved in 100 ml of ethyl acetate, filtered, concentrated to 50 ml and cooled to 0 ⁰ C, provides a precipitate. Recrystallized from ethyl acetate, the title compound is obtained therefrom.

Example 5:

The procedure according to Example 4 is repeated, wherein an equivalent amount of lead dioxide is used instead of zinc oxide.

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Example 6:

In a manner analogous to that described in the previous examples, the corresponding starting materials can be used if this is done used in almost equivalent amounts the following products are obtained:

5,7-dimethyl-1-isopropyl-4-phenyl-quinazolin-2 (IH) -one, l-isopropyl-7-methyl-4- (p-methylphenyl) -quinazolin-2 (IH) one,

I-isopropyl-7-methyl-4- (2-thienyl) -quinazolin-2 (IH) -one, 1-Cyclopropylmethyl-6-methoxy-4-phenyl-quinazolin-2 (IH) one.

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Claims (9)

"SANDOZ-PATENT-GMBH Case 600-6744 / X 7850 Loerrach Improvements in or relating to organic compounds Claims; ti /. Process for the preparation of 4-aryl-quinazolin-2 (1H) -ones, by adding a corresponding 4-aryl-5,6,7,8-tetrahydro-2 (IH) -quinazolinone is dehydrogenated with sulfur in an inert organic solvent, and which is characterized in that the dehydrogenation takes place in the presence of an inorganic metal compound in the form of an oxide, hydroxide or salt and the metal compound under the reaction conditions forms a metal sulfide, with the exception of magnesium, aluminum and alkali metal compounds. 2. Process for the preparation of compounds of the formula I, in which R _{1 is} a (C ₁ -C.) hydrocarbon radical which X XO 909810/089 R, - 2 - 600-6744 / X optionally fluorine, chlorine and bromine is mono-, di- or tri-substituted, . "Represents a monocyclic aryl and R and R are the same or different and each Hydrogen, (C.-C) alkyl or alkoxy, fluorine, Mean chlorine, bromine or trifluorinethyl or R_ and R together are a 6,7-methylenedioxy group form, by a corresponding 4-aryl-5,6,7,8-tetrahydro-2 (IH) -quinazolinone of formula II II in which R, R, R and R have the meanings mentioned above have, is dehydrogenated with sulfur in an inert organic solvent, and this is characterized is that the dehydrogenation in the presence of an inorganic metal compound in the form of an oxide, Hydroxide or salt takes place and the metal compound forms a metal sulfide under the reaction conditions, with the exception of magnesium, aluminum and alkali metal compounds. 3. Process according to claims 1 and 2, characterized in that the dehydrogenation is carried out at temperatures between 125 ° and 250 ⁰ C and the molar ratio of sulfur to the tetrahydroquinazolinone starting compound is at least 1.7: 1 and the molar ratio of the inorganic metal compound to the tetrahydrochinozalincn- 909810/0892 - 3 - 600-6744 / X Starting compound is at least 1: 1. 4. The method according to claim 3, characterized in that that the molar ratio of sulfur to the tetrahydroquinazolinone starting compound is between 1.9: 1 and 4: 1 lies. 5. The method according to claims 1-4, characterized in that that the molar ratio of the inorganic metal compound to the tetrahydroquinazolinone starting compound is between 1.8: 1 and 6: 1. 6. The method according to claim 5, characterized in that the molar ratio is between 2: 1 and 4: 1. 7. The method according to claim 6, characterized in that the molar ratio is between 2.1: 1 and 3: 1. 8. The method according to claim 1, characterized in that the (C -C) hydrocarbon radical of R, ± ö -L (C _n -C-) alkyl and optionally with fluorine, chlorine 1 6 or bromine is mono-, di- or tri-substituted or (C -C) cycloalkyl, (C -C) cycloalkylalkyl with a (C -C) cycloalkyl and with a (C -C ") alkyl part or phenyl, benzyl or phenylethyl, which is optionally mono- or with fluorine, chlorine or bromine is disubstituted. 9. The method according to claim 1, characterized in that R "is a radical of the formulas III or IV 909810/0892 - 4 - 600-6744 / X or - \ _ J- * ₂ ^IV is, in which Y and Y _{1 are} identical or different and are each hydrogen, fluorine, chlorine, bromine, (C -C) alkyl or alkoxy or trifluoromethyl, provided that if one of Y and Y _{1 represent} trifluoromethyl, the other is hydrogen and Y is hydrogen, fluorine, chlorine, bromine, (C -C) alkyl or alkoxy. ίο. Compounds of the formula I, reproduced in Claim 1 and produced by the process according to Claim 1. 909810/0892